This is a planning proposal for the support of cross-disciplinary research and education in computational biology at Berkeley. The general research themes are evolutionary genomics and macromolecular structure. Development projects are proposed in comparative genome analysis and interpretation, comparative analysis of cis-regulation and the role of gene regulation in organismal diversity, and deciphering genetic variation in protein kinases. Educational and outreach activities include a new cross-disciplinary doctoral program as well as seminars, colloquia, short courses and workshops. The training of graduate students and post-docs will be a major component of the program. The comparative genome analysis project will develop an integrated set of software tools for the comparative analysis of genomes, proteomes and regulatory pathways. These tools will be applied to assembling an increasingly accurate picture of the Tree of Life, annotating specific evolutionarily related sets of sequenced genomes, analyzing regions of genomes identified as potentially harboring genes implicated in disease, and elucidating the evolutionary and structure-function relationships among proteins. The cis-regulation project will use evolutionary comparisons to analyze transcription factor interactions with DNA, understand the design principles that define biologically active regulatory sequences and relate the organization of functional transcription factor binding sites to patterns of gene expression. The protein kinase project will develop computational protocols to discover and classify protein kinases and describe the regulatory domains that are fused to them. Computational tools will be developed to discover functional sites in protein kinases, and their predictions will be tested with genetic, biochemical and structural studies. Improved potential functions for dynamics simulations will be developed and used to classify protein kinases. Programs will be developed enabling students in departments across the computational, engineering, physical and biological sciences to complete their doctoral degree with a "Designated Emphasis in Computational and Genomic Biology." To foster interdisciplinary training and collaboration, students and post-docs in this program will work with dual mentors.